Hexahydro-6-aryl-pyrrolo[2,1-a]isoquinolines (I) comprise a very valuable class of compounds, in that they are useful for the treatment of depression in warm-blooded animals, e.g., man as disclosed in U.S. Pat. No. 4,595,688 to B. E. Maryanoff. Such compounds are of the following formula (I) and the pharmaceutically acceptable salts thereof: ##STR3## wherein R.sub.4 and R.sub.5 are the same and both are hydrogen, or different and each is selected from the group of hydrogen or lower alkyl, e.g. having 1 to 4 carbons;
R.sub.6 and R.sub.7 are the same or different and each is selected from the group of hydrogen, lower alkyl, e.g. having 1 to 4 carbons, lower alkoxy, e.g. having 1 to 4 carbons, or halogen, or else are taken together as methylenedioxy; and PA1 R.sub.8 and R.sub.9 are selected from the group of hydrogen, lower alkyl, e.g. having 1 to 6 carbons, perfluoro(lower)alkyl, e.g. having 1 to 4 carbons, lower alkoxy, e.g. having 1 to 4 carbons, carb(lower)alkoxy, e.g. having 1 to 5 carbons, lower alkylthio, e.g. having 1 to 4 carbons, lower alkylsulfonyl, e.g. having 1 to 4 carbons, nitro or halogen.
A more detailed description of such compounds of formula (I) as well as methods for their synthesis and utility are described in U.S. Pat. No. 4,595,688 which is hereby incorporated by reference. The numbering system for the various substituents, e.g. R.sub.4 and R.sub.5, conform to that in the '688 patent R.sub.1, R.sub.2 and R.sub.3 are missing from formula (I) since such positions in the '688 patent are only hydrogen herein.
The various diastereomers of each formula (I) compound are distinguished herein using the nomenclature recommended by Chemical Abstracts for representing the relative configuration of diastereomers of fused-ring compounds (.alpha./.beta. nomenclature). This requires that the stereocenter corresponding to the lowest numbered atom in the ring system (numbered according to convention) be designated .alpha. and that the remaining stereocenters be labeled .alpha. or .beta. relative to the first-assigned center. In this class of compounds, biological activity is generally found to be enhanced in one class of diastereomers in which the stereocenters at positions 6 and 10b are in a trans geometry (6.alpha.,10b.beta. configuration), see Maryanoff, B. E., et al. J. Med. Chem 1987, 30, 1433. The trans (6.alpha.,10b.beta.) and cis (6.alpha.,10b.beta.) arrangements are shown in formula (II) and (III), respectively: ##STR4## Also, biological activity is largely exhibited by one of the two possible enantiomers, that being the one with a R arrangement at the 10b position as shown in formula (II).
The various prior art synthesis methods for formula (I) compounds produce mixtures of diastereomers which are not highly enriched in the preferred trans diastereomer (II). For the compound of formula (I) where R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are hydrogen, a most favorable ratio is only about 3:1 (trans:cis) by the hydrogenation of enamine (IV) in the presence of triethylamine. The product of the reaction is the mixture of the trans diastereomer (V) and the cis (VI): ##STR5##
Other prior art processes give poorer trans/cis ratios, ranging from 1:10 to 1:2
It is an object of the present invention to provide a new process that results in high diastereoselection of the more desirable trans isomer of formula (II).